Cloning, expression, and pharmacological characterization of a novel human histamine receptor.

Using a genomics-based reverse pharmacological approach for screening orphan G-protein coupled receptors, we have identified and cloned a novel high-affinity histamine receptor. This receptor, termed AXOR35, is most closely related to the H3 histamine receptor, sharing 37% protein sequence identity. A multiple responsive element/cyclic AMP-responsive element-luciferase reporter assay was used to identify histamine as a ligand for AXOR35. When transfected into human embryonic kidney 293 cells, the AXOR35 receptor showed a strong, dose-dependent calcium mobilization response to histamine and H3 receptor agonists including imetit and immepip. Radioligand binding confirmed that the AXOR35 receptor was a high-affinity histamine receptor. The pharmacology of the AXOR35 receptor was found to closely resemble that of the H3 receptor; the major difference was that (R)-alpha-methylhistamine was a low potency agonist of the AXOR35 receptor. Thioperamide is an antagonist at AXOR 35. Expression of AXOR35 mRNA in human tissues is highest in peripheral blood mononuclear cells and in tissues likely to contain high concentrations of blood cells, such as bone marrow and lung. In situ hybridization analysis of a wide survey of mouse tissues showed that mouse AXOR35 mRNA is selectively expressed in hippocampus. The identification and localization of this new histamine receptor will expand our understanding of the physiological and pathological roles of histamine and may provide additional opportunities for pharmacological modification of these actions.

[1]  J. Schwartz,et al.  Highly potent and selective ligands for histamine H3-receptors , 1987, Nature.

[2]  M. Jackson,et al.  Cloning and functional expression of the human histamine H3 receptor. , 1999, Molecular pharmacology.

[3]  M. Uhler,et al.  Molecular cloning of a gene encoding the histamine H2 receptor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Fabienne,et al.  Differential Expression of Peroxisome Proliferator-Activated Receptors (PPARs): Tissue Distribution of PPAR-a, $3, and -y in the Adult Rat* , 2001 .

[5]  Y. Horio,et al.  Expression cloning of a cDNA encoding the bovine histamine H1 receptor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Nalwalk,et al.  Effects of naltrexone and histamine antagonists on the antinociceptive activity of the cimetidine analog SKF92374 in rats , 1997, Brain Research.

[7]  R. Egan,et al.  Identification of two H3-histamine receptor subtypes. , 1990, Molecular pharmacology.

[8]  B. Conklin,et al.  Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha. , 1993, Nature.

[9]  P. Nambi,et al.  Species differences in the binding characteristics of [125I]IRL-1620, a potent agonist specific for endothelin-B receptors. , 1994, The Journal of pharmacology and experimental therapeutics.

[10]  D. J. Beer,et al.  The influence of histamine on immune and inflammatory responses. , 1984, Advances in immunology.

[11]  L. Fitzgerald,et al.  Measurement of responses from Gi-, Gs-, or Gq-coupled receptors by a multiple response element/cAMP response element-directed reporter assay. , 1999, Analytical biochemistry.

[12]  P. Cumming,et al.  Characterization of the antinociceptive properties of cimetidine and a structural analog. , 1996, The Journal of pharmacology and experimental therapeutics.

[13]  M. Billah,et al.  The profiles of human and primate []N∝-methylhistamine binding differ from that of rodents , 1999 .

[14]  W. Wahli,et al.  Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. , 1996, Endocrinology.

[15]  Jian-guo Li,et al.  Nucleoside diphosphate kinase associated with membranes modulates μ-opioid receptor-mediated []GTPγS binding and agonist binding to μ-opioid receptor , 1999 .

[16]  E. Bissonnette,et al.  Importance of Histamine in the Cytokine Network in the Lung Through H2 and H3 Receptors: Stimulation of IL-10 Production1 , 2000, The Journal of Immunology.

[17]  O. Zuiderveld,et al.  Pharmacological characterisation of the histamine H3 receptor in the rat hippocampus , 1998, Brain Research.

[18]  B. Conklin,et al.  Substitution of three amino acids switches receptor specificity of Gqα to that of Giα , 1993, Nature.

[19]  N. Chaudhari,et al.  An Optimized Method for In Situ Hybridization with Signal Amplification That Allows the Detection of Rare mRNAs , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[20]  T. Watanabe,et al.  Binding characteristics of a histamine H3-receptor antagonist, [3H]S-methylthioperamide: comparison with [3H](R)alpha-methylhistamine binding to rat tissues. , 1994, Japanese journal of pharmacology.

[21]  A. Falus,et al.  Histamine: an early messenger in inflammatory and immune reactions. , 1992, Immunology today.

[22]  K. Melmon,et al.  A histamine derivative increases intracellular calcium mobilization and oxidative metabolism in HL-60 cells. , 1993, Immunopharmacology.

[23]  R. Leurs,et al.  Histamine homologues discriminating between two functional H3 receptor assays. Evidence for H3 receptor heterogeneity?. , 1996, The Journal of pharmacology and experimental therapeutics.

[24]  J. Chambers,et al.  Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. , 1999, Molecular pharmacology.

[25]  H. Sarau,et al.  Identification of an EDG7 variant, HOFNH30, a G-protein-coupled receptor for lysophosphatidic acid. , 2000, Biochemical and biophysical research communications.

[26]  K. Melmon,et al.  The effects of derivatives of histamine on natural suppressor cells. , 1986, Journal of immunology.

[27]  D. Bergsma,et al.  Orphan G protein-coupled receptors: a neglected opportunity for pioneer drug discovery. , 1997, Trends in pharmacological sciences.

[28]  E. Schulman,et al.  Pharmacologic characterization of a novel histamine receptor on human eosinophils. , 1994, American journal of respiratory and critical care medicine.

[29]  J. Black,et al.  Evidence that histamine homologues discriminate between H3‐receptors in guinea‐pig cerebral cortex and ileum longitudinal muscle myenteric plexus , 1999, British journal of pharmacology.

[30]  Y. Masuho,et al.  Molecular Cloning and Characterization of a Novel Type of Histamine Receptor Preferentially Expressed in Leukocytes* , 2000, The Journal of Biological Chemistry.